In the second installment of a 2-part Infertility series, 

 outlines a shared decision-making method when treating the infertile couple. “Effective treatment will depend on the diagnosis, but can range from simple to very complex,” the authors said.

“The diagnosis of the infertile couple​”

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What did you think of this month’s cover story? October 2020

My antepartum rounds reflect the impact of the pandemic - women struggling with substance abuse and mental illness fill the beds. 

One patient, wearing her designated green hospital gown that signals “at-risk” status and assigned a one-on-one sitter, explained, (

 thoughts now? I have three kids at home – two I try to make the computer work for so they can attend school, a 1-year-old, and here I am pregnant again. We lost our jobs, tensions are high, we cannot visit or see anyone, we have no help…. At times it all just boils up and I explode. Then I think life is not worth living. I get over it, but yes, I have bad thoughts.”

As demonstrated by my patients, the very measures used to prevent the spread of COVID-19 increase the risk of depression and suicidal thoughts: economic stress, social isolation, decreased access to community, barriers to mental health treatment, and illness.

According to the Centers for Disease Control and Prevention (CDC), the national rates of anxiety increased nearly four-fold from one year ago. In 1999, national rates of anxiety in adults were 8.2%, whereas data from August 19-31, 2020, are 31.4%. 

Similarly, rates for anxiety or depression have increased from 11.0% to 36.4%. All are higher in women, those with less education, and Black, Hispanic, and multiple other races.

A separate survey in June found similar rates of anxiety or depression (30.9%). In addition, 10.7% of the respondents reported “having seriously considered suicide in the prior 30 days” – these were significantly higher among those aged 18-24 (25.5%), minority racial and ethnic groups (Hispanic 18.6%; Black 15.1%) and essential workers (21.7%)(Figure 1).

Beyond its impact on our patients, it is vital to realize its effect on us as caregivers. 

As the impact of the pandemic continues, our ob/gyn practices and families are affected. Eighty-three percent of obstetrics and gynecology residents are female – the highest percentage of any specialty

 – and they are often playing a dual role as the family’s primary caregiver in addition to practicing medicine. 

Setting aside the burden of virtual schooling for both caregivers and children, the effects of social isolation and decreased access

to community are also affecting our children. They also mirror increased rates of anxiety and depression, yet may not have the access or resources for identification and treatment.

So what to do, what to do? In our practices, departments, and families, providing an opportunity for open communication and a safe space to share feelings without judgment is essential.Proactively, one of my colleagues’ practices meets biweekly with a psychologist. All of the providers gather and discuss both practice and personal stressors. Although predating the pandemic, this has been especially beneficial with an ongoing opportunity for open communication to discuss and identify solutions. These sessions help to identify feelings, conflicts, and provide strategies to communicate them effectively. They also allow a platform to discuss complications and poor patient outcomes, serving as a forum to process these deeply traumatizing events and rise, rather than stagnate, or worse, fall. We as physicians need this type of forum in order to heal ourselves.

Our patients and families deserve similar support and we should strive to help them get it. We need to provide opportunities for open communication in a safe space. Referrals to our colleagues in psychiatry and psychology are essential to ensure appropriate care. Although there is always a shortage of therapists, these at-risk populations need to be prioritized. Furthermore, we need to be on the alert for signs and symptoms of anxiety and depression in not only ourselves but also in our colleagues, families, and patients

editor-in-chief, is Professor and Vice Chair in the Department of Obstetrics and Gynecology and Chief of the Division of Maternal-Fetal Medicine at UT Southwestern Medical Center in Dallas. She holds the Gillette Professorship of Obstetrics and Gynecology.

1. Regar MA, Stanley IH, Joiner TE. Suicide Mortality and Coronavirus Disease 2019—A Perfect Storm? 

. Published online April 10, 2020. doi:10.1001/jamapsychiatry.2020.1060

2. Centers for Disease Control and Prevention. National Center for Health Statistics. Accessed Sept. 21, 2020. https://www.cdc.gov/nchs/covid19/pulse/mental-health.htm

3. Czeisler ME, Rashon I, Petrosky E, et al. Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic — United States, June 24–30, 2020 CDC MMWR Aug 14, 2020 vol 69, No. 32

4. Association of American Medical Colleges. Percentage of Women Residents by Specialty 2018. Accessed Sept. 21, 2020. https://www.aamc.org/sites/default/files/aa-data-reports-state-of-women-residents-specialty-2018_0.jpg

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The very measures used to prevent the spread of COVID-19 increase the risk of depression and suicidal thoughts: economic stress, social isolation, decreased access to community, barriers to mental health treatment, and illness.

Mental health support is critical during pandemic

On March 24, 2014, a 26-year-old female patient began treatment with the defendants’ practice, when she was examined and evaluated by Defendant A. The patient completed a questionnaire, in which she documented the reason for the appointment as “irregular period/other symptoms having to do with that.” She did not specify any other symptoms. 

The patient reported her last menstrual period (LMP) as occurring on Nov. 29 to Dec. 8, 2013, and again on Feb. 3, 2014. She had no past obstetrical history. Her gynecologic history was negative for sexually transmitted diseases (STD) and pelvic inflammatory disease. Her medical history was pertinent for anxiety, but she was no longer on fluoxetine. 

Her mother had ovarian cancer but both parents were alive and well. The patient smoked ½ packs of cigarettes per day. She had no known drug allergies. 

Defendant A referred her for lab work including a complete metabolic panel, complete blood count (CBC), and hormone levels. Bloodwork was performed on April 10, 2014 and reported to Defendant A on April 16. 

The triiodothyronine (T3) uptake was high at 36. The luteinizing hormone (LH) was 1.8 with follicle-stimulating hormone (FSH) at 8.0. The prolactin was 12, dehydroepiandrosterone 235, and testosterone 17. The lab report contains the following reference ranges: follicular phase (2.5-10.2 mIU/mL); mid-cycle peak (3.1-17.7 mIU/mL); luteal phase (1.5-9.1 mIU/mL); and postmenopausal (23-116.3 mIU/mL). 

Prolactin levels were reported as 12.0 ng/mL, with a reference range of post-menopausal (2-20 ng/mL); pregnant (10-209 ng/mL); non-pregnant (3-39 ng/mL).On April 16, the patient also presented to the codefendant’s perinatal services clinic for a pelvic sonogram due to amenorrhea “on and off for the past 6 months.” 

Her LMP was documented as April 5. The impression was normal pelvic sonogram with no adnexal masses noted. There was no free fluid seen. The endometrial stripe was within normal limits. Clinical correlation and follow up was recommended.

A progesterone level was drawn on April 29. The result was .4 ng/mL, with reference ranges as follows: Follicular phase (.0-1.1 ng/mL), mid-follicular (0.0 – 1.0 ng/mL), mid-cycle (.5-1.7 ng/mL), luteal phase (1.0-21 ng/mL), mid-luteal (6.0-24 ng/mL), post-menopausal (0.0-1.0 ng/mL), oral contraceptives (.3-.9 ng/mL).

On Sept. 6, the patient presented to her primary care physician (PCP) with complaints of a pelvic infection that had been diagnosed by a walk-in clinic the day earlier. Her PCP advised her to follow up with her gynecologist and follow the antibiotics recommendations of the walk-in clinic. There was no discussion of amenorrhea documented in the records at this visit.

Approximately six weeks later, on Oct. 27, 

the patient returned to the defendants’ practice and was evaluated by Defendant A. The exam and findings were generally negative. Cultures were taken for gonorrhea and chlamydia, as well as urine culture and sensitivity tests. 

Defendant A diagnosed a yeast infection and prescribed fluconazole. The cultures for gonorrhea, chlamydia and a urine culture were negative.

On Dec. 15, the patient presented to her PCP with complaints of missed periods, requesting a pregnancy test. Her PCP did a pregnancy test, which was negative. 

He recommended follow up with her ob/gyn. On Feb. 3, 2015, she again returned to her PCP with complaints of not feeling well, including headache and anxiety. She was evaluated and the working plan included follow-up with her ob/gyn, diet, exercise, water intake, and to go to the ER if her symptoms persisted.

On May 11, she presented again to her PCP’s office for “routine gynecological treatment.” She reported she was “feeling well and with no complaints.” 

Her LMP was documented as April 27. The plan was for blood work including CBC, a metabolic panel, STD screenings, thyroid levels, and to return to the office for routine care as needed.

On May 18, nearly six months after her PCP first advised her to return to her ob/gyn for follow-up care, the patient returned to Defendant A’s office, this time for a possible yeast infection with itchy discharge. Fluconazole 150 mg by mouth once a day was prescribed. 

On June 1, the patient returned with concerns about a possible lost tampon. Defendant A performed an internal exam, found no lost tampon, and prescribed metronidazole 0.75 vaginally at bedtime for five days for bacterial vaginosis.

On Aug. 27, she returned to her PCP, for a sick visit due to an upper respiratory infection. Her last menstrual period was documented as Aug. 6.

On Nov. 5, the patient returned to the defendants’ practice and was seen by Defendant B. The chief complaint was bacterial vaginosis. 

A vaginal culture and urine culture were obtained. Defendant B prescribed metronidazole, and nystatin and triamcinolone acetonide cream. Defendant B also discussed birth control options with the patient. 

 she had bad experiences with birth control in the past, and was reluctant to go on them again. On Dec. 7, the patient saw Defendant A. According to the record, the plan was to check labs and birth control pills were prescribed.On Dec. 14, she went for blood work, which came back abnormal. The FSH was in the menopausal range at 25.1 IU/L.

On Dec. 21, the patient called the defendants’ clinic, stating that she had a repeat bacterial infection. A prescription for metronidazole was called to her pharmacy. 

This was the last contact that the plaintiff had with the defendants’ office.

On Feb. 1, 2016, the patient presented for the first time to the offices of non-party ob/gyn.She reported her last menstrual period started on Jan. 18, 2016. She reported frequent bacterial infections and amenorrhea. She was diagnosed with bacterial vaginosis and prescribed clindamycin. No further workup was performed at this time, despite the report of amenorrhea during this visit.

Six months later, on Aug. 11, she returned to non-party ob/gyn’s office for further evaluation and treatment of a yeast infection. 

At this visit, she was sent for further blood work. FSH was reported as 70.9 mIU/mL. The lab report contained the following reference ranges: follicular phase (3.5-12.5 mIU/mL); mid-cycle peak (4.7 – 21.5 mIU/mL); luteal phase (1.7-7.7 mIU/mL); and postmenopausal (25.8-134.8 mIU/mL).

On Aug. 21, the patient returned to non-party ob/gyn’s office. Her last menstrual cycle had been 3 months earlier. The plan was to repeat labs in one month and then start birth control pills. On Aug. 22, the patient had a sonogram with non-party ob/gyn that was interpreted to be within normal limits. That was the last contact the plaintiff had with non-party ob/gyn’s office.

On Sept. 1, the patient presented to a non-party specialist for a fertility evaluation. She reported her last menstrual period as June 10, 2016. 

On Sept. 7, her ovaries were “quiet.” 

On Sept. 21, her right and left ovaries showed 2-3 follicles each. In 2017, she went to see a new ob/gyn, who treated her symptoms with an estradiol transdermal system and progesterone. She last had her period in the summer of 2018.

 from March 2014 through December 2015, the defendants failed to timeline and properly consider lab and sonogram results, failed to order further studies, failed to refer the plaintiff to a fertility specialist, and failed to consider her complaints and concerns. As a result, she claimed she was put into early ovarian failure and rendered infertile.

The plaintiff testified that prior to her treatment with Defendant B she had some “weird body issues” including body aches, joint pains as well as headaches, fatigue, and anxiety. 

The symptoms began to snowball into one another; and she reported that hot flashes and dizziness started around July of 2016. She reported that from about 2010 to 2013 her periods were regular on a 28-31 day cycle lasting 4-6 days, and she would have some typical symptoms of PMS such as cramping, but no other complaints of abnormal periods. 

In 2014, she started noticing abnormal periods. This is when she started treatment with the defendants. She defined abnormal as “not as frequent and not on a schedule.” She also started suffering from frequent bacterial infections. 

She also testified that during one visit Defendant A stated that she should “consider yourself lucky. No girl wants her period. Come back and see me when you want kids.” 

She recalled a discussion over being put on birth control, but she did not want to go on it because of past experiences. She was told by subsequent physicians that she had the FSH level of a “menopausal woman.” She also testified that had she known earlier she could have used fertility-preserving treatment such as freezing her eggs. 

The fertility specialist advised her that it was too late for egg retrieval; however, she was a good candidate for in vitro fertilization. 

Unfortunately, Defendant A passed away shortly after the commencement of the litigation. Defendant B had no recollection of this patient, having only treated her on one occasion during the time period in question. He felt strongly that the appropriate workup was done, there was no reason to repeat the testing after April 2014, and when it was repeated in late 2015 and came back suspicious, the patient never returned to the office.

. He explained that irregular periods in patients of this age are very common and ovarian failure is “last on the list” within the differential. He said that stress is the primary reason for irregular periods and they may also be the result of weight loss, exercise, and a host of other factors. 

For that reason, the standard of care does not call for automatic lab testing when patients present with these complaints. The lab results consisted of an FSH of 8.0 and an LH of 1.8. The patient also had low progesterone and Defendant A put her on medication for that reason. 

An FSH of 8.0 was perfectly normal and no further workup was required at that point. While the plaintiff took the position that further lab work should have been done when the patient returned on several occasions up through December 2015 (which is the next time her FSH was tested), our expert maintained that no additional testing was needed. 

There was evidence that the patient did continue to have periods.For example, when a sonogram was done on April 14, the LMP was listed as April 5, 2014, and there was a June 1, 2015, visit for a possible lost tampon. 

Additionally, after the patient left the defendants’ care in December 2015, there was an LMP listed as Jan. 18, 2016, at her subsequent treater’s office. Once the initial labs came back within normal limits and once the sonogram on April 14 showed normal ovaries with a left-side ovary that was ovulating, there was no reason to suspect the patient was going into ovarian failure. 

He felt the patient should have been advised of her elevated FSH in August 2015, but that at that point the die was cast and it would not have altered the outcome.

After all depositions were concluded, we moved for summary judgment dismissal of the case. While the motion was pending, but prior to opposing, the patient’s attorney contacted our office seeking a reasonable settlement as to the estate of Defendant A. 

Putting aside the opportunity to resolve this case for less than the cost of trying it, the matter settled primarily for two reasons. 

The first reason was the absence of any documentation by the defendants of awareness or follow-up with the patient for the elevated FSH in November 2015. Whether or not the die was cast, as it were, documenting acknowledgment of the abnormal results and discussion with the patient still was required. 

where Defendant A passed before he could testify in response to the patient’s assertion that he downplayed her complaints and test results to her detriment. 

Absent an opportunity to produce a witness to rebut those assertions, and given the reasonable demand, the decision was made to resolve the matter rather than risk a sympathetic verdict, 

is a partner at Aaronson, Rappaport, Feinstein & Deutsch, LLP in New York City, specializing in medical malpractice defense and healthcare litigation. This case was handled by one of his partners.

The outcome in this case underscores the need for solid documentation, especially when one of the defendants has passed.

Was this a failure to diagnose ovarian failure? 

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality. The estimated incidence of VTE during pregnancy and the postpartum period is 1 to 2 per 1,000 deliveries.

The risk of VTE is particularly high during the postpartum period and especially following cesarean delivery.

There is considerable variation in the approach to VTE prophylaxis in pregnancy, including following cesarean delivery. Recent guidelines by various professional organizations provide conflicting recommendations based on low-grade evidence, mainly from observational data. 

At present, the available VTE risk stratification tools used to decide for or against pharmacological prophylaxis have not been validated in women undergoing cesarean delivery. Individualization of care is recommended for women at very high risk of VTE.

Q| What are the current guidelines for VTE prophylaxis following cesarean delivery?

Several guidelines define risk factors for VTE, including those summarized in Table 1 from the American College of Chest Physicians (ACCP), Royal College of Obstetricians and Gynaecologists (RCOG), and National Partnership for Maternal Safety (NPMS).

The American College of Obstetricians and Gynecologists (ACOG) recommends that all women undergoing a cesarean delivery receive mechanical prophylaxis with the use of pneumatic sequential compression devices started preoperatively and continued until the patient is ambulatory.

The use of combined pharmacological and mechanical prophylaxis may also be supported based on individual risk assessment. ACOG does not endorse any specific risk stratification guidelines. Hospitals are encouraged to evaluate women for VTE risk factors and to implement a prophylaxis protocol weighing benefits, harms, and cost-effectiveness. If VTE risk factors persist during the postpartum period, up to 6 weeks of pharmacological prophylaxis should be considered.

The ACCP suggests that the benefits of thromboprophylaxis outweigh potential harm when the absolute risk of VTE is 3% or higher.

 The presence of 1 major risk factor, 1 minor risk factor in the setting of an emergent cesarean delivery, or 2 or more minor risk factors suggests a VTE risk above 3%. 

For women undergoing cesarean delivery with no risk factors for VTE, ACCP recommends no prophylaxis other than early mobilization. 

In women at very high risk for VTE, combined pharmacological and mechanical prophylaxis is suggested. If VTE risk factors persist during the postpartum period, up to 6 weeks of prophylaxis is suggested.

The RCOG recommends thromboprophylaxis with low-molecular-weight heparin (LMWH) for 10 days after delivery should be considered for all women who have had cesarean sections and those having an elective cesarean section who have any additional risk factors.4 Prophylaxis with LMWH is recommended for 10 days following delivery in intermediate-risk women and for at least 6 weeks following delivery in high-risk women.

The NPMS recommends universal pneumatic compression devices for all women undergoing cesarean deliveries.

The addition of pharmacological prophylaxis may be considered for women at high risk of VTE based on the use of either the RCOG guidelines or the modified Caprini scoring system. Hospitals may consider providing pharmacological VTE prophylaxis to all women undergoing a cesarean delivery because of the challenges in consistently identifying women with VTE risk factors.

Q| Is there sufficient evidence to recommend one specific guideline over the other?

In general, all women with a previous episode of VTE require prophylactic doses of LMWH or unfractionated heparin (UFH) for at least 6 weeks postpartum. Women with no previous personal history of VTE but who have tested positive for one of the high-risk inherited thrombophilias (antithrombin III deficiency, homozygous Factor V Leiden or G20210A, or heterozygous for both Factor V Leiden and G20210A) or who have a low-risk thrombophilia should also receive pharmacological VTE prophylaxis following cesarean delivery. 

Women with a previous diagnosis of antiphospholipid antibody syndrome should receive prophylactic or therapeutic doses of heparin (depending on previous history of VTE) during the puerperium irrespective of mode of delivery.

The main discrepancy among current guidelines concerns pharmacologic prophylaxis for women with no history of VTE and no inherited or acquired thrombophilia. Recommendations differ in part because they are based on observational studies and expert opinion due to a lack of clinical trial data. 

This presents a challenge for determining the true incidence of VTE and accurately assessing the risk-benefit ratio of pharmacological prophylaxis following cesarean delivery. The potential benefit of pharmacological prophylaxis needs to be weighed against the potential for adverse outcomes associated with the intervention. 

For instance, the use of pharmacological VTE prophylaxis following cesarean delivery has been associated with increased rates of wound separation and wound hematomas. In the absence of adequately powered clinical trials, accurate calculations of the number needed to treat (NNT) and number needed to harm (NNH) are limited. 

However, the available evidence suggests that the NNH may be lower than the NNT in most scenarios, particularly in the absence of risk factors or the presence of only a minor risk factor. 

Further, administrative and retrospective data obtained from analysis of large databases may overestimate the incidence of VTE, resulting in a similar overestimation of the benefit of any intervention aimed at preventing it.

Another consideration in making recommendations is that the use of risk assessment models (eg, Caprini and Padua) to predict VTE following cesarean delivery has not been adequately studied. 

The authors of a recent study questioning their utility during the peripartum period suggest the establishment of a maternal clinical registry and more extensive research to identify optimal models with which to predict VTE risk in the obstetrical population.

At present, the available evidence to suggest that universal (or near universal) pharmacological VTE prophylaxis effectively reduces maternal mortality is limited.

 Any attributable benefit of universal pharmacological VTE prophylaxis after cesarean delivery in maternal mortality will likely be low due to the rarity of the event. 

A recent study reported only 1 maternal death from VTE among 465,880 women undergoing a cesarean delivery when all women received mechanical prophylaxis (eg, sequential compression devices).

Q| Which pharmacological agents are commonly used for prophylaxis of venous thromboembolism?

The two most common agents used for VTE prophylaxis are LMWH and UFH. Current guidelines recommend LMWH (eg, enoxaparin) as the first-line pharmacological agent.

Enoxaparin is not recommended in patients with significant renal dysfunction, defined as creatinine clearance less than 30 mL/min. 

Compared with UFH, enoxaparin has the advantage of better bioavailability, longer half-life, more predictable anticoagulation effect, less bleeding risks, and less risk of heparin-induced thrombocytopenia and osteopenia. 

For prophylaxis purposes, the recommended enoxaparin dosage is typically 40 mg subcutaneously once a day. Obese women may require higher doses; however, the optimal dose is unknown. Some evidence supports the use of intermediate doses of enoxaparin (40 mg subcutaneously every 12 hours) for obese women.

UFH is a good choice in women with renal disease. Recommended prophylactic dosages range from 5000 to 10,000 units subcutaneously every 12 hours depending on gestational age (5000 units subcutaneously every 12 hours in the first trimester, 7500 units subcutaneously every 12 hours in the second trimester, and 10,000 units subcutaneously every 12 hours during the third trimester). 

In the postpartum period, doses of 5000 units subcutaneously every 8–12 hours are commonly utilized. There are insufficient data to recommend the use of new oral anticoagulants (eg, apixaban, rivaroxaban, dabigatran) during the postpartum period.

Q| When is the optimal time to start thromboembolism prophylaxis after a cesarean delivery?

Current ACOG guidelines recommend starting VTE mechanical prophylaxis with sequential compression devices preoperatively in all women undergoing a cesarean delivery.

The Society for Obstetric Anesthesia and Perinatology (SOAP) has addressed the optimal interval between neuraxial anesthesia and initiation of VTE pharmacological prophylaxis to prevent development of spinal or epidural hematomas.

Prophylactic doses of enoxaparin (40 mg subcutaneously every day) may be started postoperatively as soon as 4 hours after catheter removal but not earlier than 12 hours after the block was performed. Intermediate doses of enoxaparin (40 mg subcutaneously every 12 hours) and therapeutic doses may also be started as soon as 4 hours after catheter removal but not earlier than 24 hours after the block was performed. Prophylactic doses of UFH may be started as early as 1 hour after removal of the neuraxial catheter.

In addition to concerns about spinal hematomas, timing to start VTE prophylaxis should also consider the risk of postoperative bleeding. 

With prophylactic doses of anticoagulation, bleeding complications are usually mild and rarely result in life-threatening hemorrhage, unlike bleeding risks with the use of full-dose anticoagulation in the postoperative period. 

In cases with significant intraoperative bleeding complications, the decision of when to start pharmacological prophylaxis (if indicated) must be individualized, while recognizing that postpartum hemorrhage, blood transfusion, and prolonged surgery are risk factors for VTE. In these cases, initiation of UFH, which is reversible and has a shorter half-life, may be prudent.

VTE remains an important cause of maternal morbidity and mortality during pregnancy and the postpartum period. 

The use of mechanical prophylaxis sequential compression devices is an inexpensive, safe intervention and should be used in all women undergoing cesarean delivery until the woman is fully ambulatory. 

The decision to add pharmacological prophylaxis depends on the presence or absence of certain risk factors. Women with a previous personal history of deep venous thrombosis or pulmonary embolism and women with a personal history of an inherited thrombophilia should receive pharmacological prophylaxis following cesarean delivery. 

The use of universal or near-universal pharmacological prophylaxis for women undergoing cesarean delivery, other than those with a previous thrombosis or an inherited thrombophilia, cannot be recommended until further studies demonstrate that such a strategy is beneficial. 

Created in partnership with the Society for Maternal-Fetal Medicine. SMFM was established in 1977 to “give Maternal-Fetal Medicine (MFM) physicians and scientists a place to share knowledge, research and clinical best practices in order to improve care for moms and babies.”

Rodger M. Pregnancy and venous thromboembolism: 'TIPPS' for risk stratification. Hematology American Society of Hematology Education Program 2014;2014:387-92.

American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy. Obstetrics and gynecology 2018;132:e1-e17.

Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S-e736S.

Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. (Accessed February 4, 2019, at 

https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg37a/

D'Alton ME, Friedman AM, Smiley RM, et al. National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism. Obstetrics and gynecology 2016;128:688-98.

Tran JP, Stribling SS, Ibezim UC, et al. Performance of Risk Assessment Models for Peripartum Thromboprophylaxis. Reprod Sci 2018:1933719118813197.

Bain E, Wilson A, Tooher R, Gates S, Davis LJ, Middleton P. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. The Cochrane database of systematic reviews 2014:Cd001689.

Clark SL, Christmas JT, Frye DR, Meyers JA, Perlin JB. Maternal mortality in the United States: predictability and the impact of protocols on fatal postcesarean pulmonary embolism and hypertension-related intracranial hemorrhage. American journal of obstetrics and gynecology 2014;211:32.e1-9.

Leffert L, Butwick A, Carvalho B, et al. The Society for Obstetric Anesthesia and Perinatology Consensus Statement on the Anesthetic Management of Pregnant and Postpartum Women Receiving Thromboprophylaxis or Higher Dose Anticoagulants. Anesthesia and analgesia 2018;126:928-44.

The risk of venous thromboembolism is particularly high during the postpartum period and especially following cesarean delivery. 

Society for Maternal-Fetal Medicine Consult Series #51: Thromboembolism prophylaxis for cesarean delivery

The path that led to American women favoring compounded bioidentical hormone therapy (cBHT) is rooted in several important historical factors. The Dietary Supplement Health and Education Act of 1994 specifically exempted compounded hormones from being considered pharmaceuticals; instead, they were put into the same category as dietary supplements. 

This designation requires far less rigor in terms of quality control, no need for adverse event reporting, and carries no requirements for potential conflicts of interest disclosures. Penalties for false advertising are rare.

In 2002, the Women’s Health Initiative (WHI) showed that estrogen and progesterone were ineffective as preventives for cardiovascular disease for women and confirmed that ‘conventional’, FDA-approved forms of hormone therapy carried health risks. 

Overall, hormone therapy caused net harm or gave no benefit to most of the women who had been taking it for treatment other than for symptoms.

 As a result, millions of women abruptly abandoned their hormone therapy. Many doctors who had prescribed it for preventive purposes were loath to accept the WHI data. 

The information gap was filled by cBHT. Because cBHT products were now dietary supplements, they were not subject to FDA approval; they had no restraints on proof of claim or efficacy and had no adverse event reporting requirements. 

Moreover, the claim that cBHT, which contained ‘natural’ –as opposed to ‘synthetic’ hormones used in research trials such as the WHI—developed great resonance in the consumer sphere. 

The concept that naturally occurring hormones were harmless began to be promulgated and provided women with a new, alternative treatment that seemed to be superior.

Although many naturally occurring hormone products got approved by the FDA during and immediately after the WHI and rapidly became widely available, 

the cBHT industry effectively used internet-based marketing and repetition of partial truths to garner a significant portion of the dwindling hormone therapy market. 

The mythology that the hormones used in the WHI were simply the 

hormones, and alternative cBHT products had no such side effects or risks and would, indeed, prevent aging, was widely and successfully marketed such that current estimates are that one-third to half of the national use of menopausal hormone therapy is cBHT.

‘Natural’ hormones have become highly desired by consumers, and are incorrectly viewed as without risk, in comparison to FDA-approved ‘synthetics’ used in many research trials.

Many cBHT prescribers and compounders have financial interest in prescribing and continuing therapy. 

Consumers may be recommended to use a proprietary cBHT formulation as well as a panel of ‘customized’ proprietary blood or saliva tests to follow hormone levels, with no requirement for patient disclosure. Prescribing proprietary cBHT preparations for a profit creates an overt conflict of interest and may violate professional ethics.

Due to several concerns raised by these ongoing practices, the National Academies of Sciences, Engineering, and Medicine (NASEM)

 of the field, gathering data and taking in-person testimony from pharmacists, practitioners, and patients. 

Their recommendations recently have been released and are supported by the North American Menopause Society (NAMS).

The chief recommendations relevant to many ob/gyns are summarized below and offer an excellent starting point to rein in potentially harmful medical practice in our field.

1. Review select bioidentical hormone therapies and dosage forms as candidates for the FDA Difficult to Compound list.

Drugs considered ‘difficult to compound’ are defined as “drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs.”

The NASEM report suggests the Pharmacy Compounding Advisory Committee (PCAC) review the following cBHT hormones as candidates for this list: estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone, pregnenolone, progesterone, testosterone, testosterone cypionate, and testosterone propionate. They also recommend that all cBHT in pellet form be added to this list.

The six criteria presented to the PCAC for evaluating whether a drug product or category of drug products is demonstrably difficult to compound are complexity of the:

The ‘difficult to compound’ designation prevents compounding pharmacies from making cBHT products unless they are listed as a manufacturer. 

This recommendation is the first step towards improved quality control

, which is important for cBHT as these commonly used preparations have a dearth of data specifically related to bioavailability and product-to-product variability given drug formulations differ and quality control varies from formulation to formulation in currently unknown ways.

2. Improve education for prescribers and pharmacists who market, prescribe, compound, and dispense cBHT preparations.

NASEM recommends that State medical boards and professional medical societies advocate for state-level certification for those who want to begin or continue prescribing. 

Additionally, professional societies (AMA, NAMS) that are not-for-profit could help establish evidence-based recommendations and guidelines. Education from industry is discouraged. Education would include identification of safe formulations and contraindications to treatment, description of conflicts of interest, and reasoning for when to consider cBHT over FDA-approved products.

Related: Hear from Dr. Santoro as she discusses highlights from the 2020 North American Menopause Society (NAMS) Annual Meeting.

Although prescribers are responding to patient demand, this does not supersede practice informed by evidence. Given this breach in obligation to patient safety, it is possible that prescribers could face consequences including invalidation of malpractice insurance, personal liability, or possible criminal charges.

3. Additional federal and state-level oversight should be implemented to better ad

dress public health and clinical concerns regarding the safety and effectiveness of compounded cBHT.

The report calls on the National Association of Boards of Pharmacy (NABP) and state boards of pharmacy to expand and improve oversight and standardization. 

Among the most significant suggested measure is that cBHT products include an insert containing critical details about the preparation, including active ingredients and a statement that the preparation is not FDA approved and therefore lacks the rigorous dosage, safety and efficacy data required by the FDA. 

Pharmacies are called upon to disclose their good manufacturing practices or United States Pharmacopeia (USP) designation and to include contact information for the pharmacy and those responsible for quality and safety.

Boxed warnings for adverse effects identical to that required for FDA-approved estrogens, androgens and progestins was recommended. Pharmacies providing cBHT were also called upon to create a robust methodology for 

 of adverse events, as well as make that information available to the public. 

There is no current insight into the prevalence of such events as they are not reported or available to the consumer. NASEM calls for required adverse event reporting of cBHT to state boards of pharmacy as well as to MedWatch and the FDA Adverse Event Reporting System. 

This would allow states to respond to these issues locally.

Lastly, all states should adopt USP standards to meet minimum quality standards for sterile and non-sterile cBHT preparations.

4. Collect and disclose conflicts of interest.

cBHT is often sold directly by the prescriber, which violates professional ethical conduct and is a clear example of a conflict of interest (COI).

Many providers of cBHT are physicians and advanced practice providers with credentials that patients believe to mean that they are well informed and practicing safe medicine. 

Disclosures of COI should be publicly available and disclosed to patients at the point of care. 

NASEM also recommends that state licensing boards collect and make public financial relationships so that these COIs are easily accessible to all consumers.

5. Strengthen and expand the evidence base on the safety, effectiveness, and use of cBHT preparations.

NASEM calls for increased engagement in research to generate a comprehensive evidence base for cBHT use. Assuming patient interest is here to stay, we need to provide consumers with the 

same breadth of safety data and industry accountability 

This goal will require funding and clinical research with high-quality trials, generation of bioavailability data of active ingredients, and adverse event reporting. These trials should be approved and registered by the Institutional Review Board (IRB).

6. Restrict the use of cBHT preparations.

There are select scenarios in which compounding is helpful. Some people may have an allergy to an active ingredient in all possible appropriate FDA approved formulations, and this is the most common reason to use compounded drugs in all categories. 

Other users may also require a dosage unavailable via FDA approved formulation. cBHT use should be limited to these select scenarios. 

, it should be made clear that compounded formulations are not FDA approved and thus have limited safety and efficacy data. 

patient preference alone should not be a reason to prescribe cBHT

. We understand there is patient demand, but educated decision making and doing no harm must take precedence.

The 350-page NASEM report recommends long-overdue measures that will protect consumers from unsafe health outcomes. 

The compounded bioidentical hormone industry needs major changes in oversight to keep consumers safe.

Vol 65 No 10

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